神经系统seipin缺失诱发精神迟滞的分子机制研究

Congenital generalized lipodystrophy (CGL) type II by mutation in the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene that encodes seipin is characterized by near-total loss of adipose tissue and mental retardation (cognitive deficiency and affective disorders). Our study reported that systemic seipin-deficient (seipin-KO) mice showed severe lipodystrophy, depression-anxiety behaviors and cognitive deficiency. By contrast, fat-specific seipin knockout (seipin-f-KO) mice had generalized lipodystrophy without changes in cognitive and affective behaviors. Neuron-specific seipin knockout (seipin-n-KO) male mice, but not females, appeared cognitive deficiency and affective disorders without lipodystrophy. (1) The seipin is highly expressed in the central nervous system including cortex, hippocampus and hypothalamus. (2) The male seipin-nKO mice showed the reduction of peroxisome proliferator-activated receptor gamma (PPARγ) expression in hippocampus and newly generated neuronal cells with abnormal differentiation of progenitor cells in hippocampal dentate gyrus, dysfunction of glutamate receptor and enhancement of endoplasmic reticulum (ER) stress in hypothalamic neurons. From basic neuroscience (using seipin-KO mice, seipin-f-KO mice and seipin-n-KO mice) to clinical research (CGL-II patients), this study will focuse on exploring influence of lacking seipon on hippocampal neurogenesis, expression and function of glutamate receptors and GABAA receptors, synaptic plasticity, regulation of hypothalamic-pituitary-adrenal (HPA) axis and the underlying mechanisms. Expected outcomes: the identification of molecular mechanisms underlying lack of neuronal seipin leading to mental retardation will provide highly relevant information for treating cognitive deficience and affective disorders in CGL-II patients.

先天性全身脂肪营养不良(CGL)II型是由seipin 基因突变导致脂肪萎缩和精神迟滞(智力低下、情感障碍)为临床特征的常染色体隐性遗传病。seipin基因敲除小鼠发生脂肪减少、抑郁焦虑和认知障碍；脂肪seipin敲除引起脂肪萎缩不伴有精神迟滞；神经seipin敲除可诱发抑郁焦虑和认知障碍，没有脂肪减少。我们首次报道了神经系统seipin缺失诱发精神迟滞。基于①seipin在大脑皮质、海马和下丘脑高表达的特征，②神经seipin缺失导致海马PPARγ低表达、新生神经细胞减少、谷氨酸受体下调和下丘脑内质网应激的预试验结果，本课题将以海马的神经再生、皮层-海马突触结构和功能、下丘脑-垂体-肾上腺皮质轴为切入点，从基础（seipin基因敲除小鼠）到临床（II型CGL患者）系统地研究神经系统seipin缺失诱发智力低下、抑郁和焦虑的机制，确定其关键分子靶点，为II型CGL精神迟滞的治疗提供新策略。

先天性全身脂肪营养不良是一种脂肪缺失的常染色体隐性遗传病。2型CGL（CGL2）的关键发病机制是seipin基因的无义突变，主要临床特征有脂肪缺失、胰岛素抵抗和精神发育迟滞。本课题组在2014年首先报道了，seipin基因敲除引起认知障碍和抑郁样行为——精神发育迟滞。因为seipin基因敲除引起了全身糖脂代谢的异常，因此本课题分别构建全身性，和脂肪细胞或神经细胞条件性seipin基因敲除小鼠，探讨seipin 基因缺失诱发精神迟滞的分子机制。本课题的研究结果证明，①seipin缺失减少PPARγ表达，通过下调ERK2-CyclinA和PPARγ-Wnt3信号通路影响海马干细胞的增殖和前体细胞的神经元分化；②雌激素拮抗seipin缺失引起的PPARγ表达抑制，改善seipin基因敲除小鼠的抑郁样行为；③seipin缺失通过减少PPARγ和BDNF水平，抑制海马AMPA受体表达和ERK-CREB信号通路，导致突触可塑性LTP诱导和认知障碍；④星型胶质细胞的seipin缺失通过减少PPARγ能提高GSK-3β活性和IL-6及TNF-α水平，促进Aβ诱导的神经炎症和细胞毒性；⑤seipin缺失通过降低中脑多巴胺神经元PPARγ表达能激活GSK3β信号，促进αSyn聚集和磷酸化，引起多巴胺神经元死亡，造成运动协调障碍；⑥seipin缺失通过PPARγ的低表达能增强海马神经元mTOR活化，抑制自噬体形成促进tau蛋白磷酸化，同时seipin缺失引起的胰岛素抵抗也影响tau蛋白磷酸化；⑦seipin缺失通过降低胰岛β细胞的PPARγ表达，能抑制胰岛素合成和释放，导致葡萄糖耐量降低；⑧神经细胞seipin缺失能抑制PPARγ介导的下丘脑催乳素表达，降低下丘脑厌食肽SIM1的合成，导致出生后多食性肥胖和胰岛素抵抗。项目执行期间，申请人作为通讯作者共发表SCI论文29篇（影响因子>5分=15篇），阐明了神经细胞seipin 基因缺失或seipin 基因缺失的代谢异常诱发精神迟滞的分子机制。